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Disease-associated c-MYC downregulation in human disorders of transcriptional regulation.

Cornelia de Lange syndrome (CdLS) is a rare multiorgan developmental
disorder caused by pathogenic variants in cohesin genes. It is a
genetically and clinically heterogeneous dominant (both autosomal and
X-linked) rare disease. Increasing experimental evidence indicates that
CdLS is caused by a combination of factors, such as gene expression
dysregulation, accumulation of cellular damage and cellular aging, which
collectively contribute to the CdLS phenotype. The CdLS phenotype overlaps
with a number of related diagnoses such as KBG syndrome and
Rubinstein-Taybi syndrome both caused by variants in chromatin-associated
factors other than cohesin. The molecular basis underlying these
overlapping phenotypes is not clearly defined. Here, we found that cells
from individuals with CdLS and CdLS-related diagnoses are characterized by
global transcription disturbance and share common dysregulated pathways.
Intriguingly, c-MYC (subsequently referred to as MYC) is downregulated in
all cell lines and represents a convergent hub lying at the center of
dysregulated pathways. Subsequent treatment with estradiol restores MYC
expression by modulating cohesin occupancy at its promoter region. In
addition, MYC activation leads to modification in expression in hundreds of
genes, which in turn reduce the oxidative stress level and genome
instability. Together, these results show that MYC plays a pivotal role in
the etiopathogenesis of CdLS and CdLS-related diagnoses and represents a
potential therapeutic target for these conditions.

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